The present invention relates to the use of 2-aminothiazoline derivatives of formula (I): 
or pharmaceutically acceptable salts thereof, as inhibitors of inducible NO-synthase.
The subject of the invention is the use of 2-aminothiazoline derivatives of formula (I) and pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions intended for preventing and treating diseases in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 or iNOS) is involved, the pharmaceutical compositions containing the novel 2-aminothiazoline derivatives and the pharmaceutically acceptable salts thereof, and the novel 2-aminothiazoline derivatives and the pharmaceutically acceptable salts thereof.
Nitric oxide (NO) is a diffusable radical involved in many physiological and pathological processes. It is synthesized by oxidation of L-arginine, this reaction being catalyzed by a family of enzymes known as nitric oxide synthases or NO-synthases (NOSs), which is referenced in the international enzyme nomenclature system under the number E.C. 1.14.13.39.
Three NOS isoforms, two of which are constitutive and one inducible, are known:
a neuronal NOS (NOS-1 or NNOS) was originally isolated and cloned from nerve tissue in which it is a constitutive enzyme. NOS-1 produces NO in response to various physiological stimuli such as the activation of membrane receptors according to a mechanism dependent on calcium and on calmodulin;
an inducible NOS (NOS-2 or iNOS) can be induced in response to immunological stimuli such as, for example, cytokines or bacterial antigens in various cells such as, for example, macrophages, endothelial cells, hepatocytes, glial cells, as well as many other types of cell. The activity of this isoform is not regulated by calcium. Consequently, once induced, it produces large amounts of NO over prolonged periods.
an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium/calmodulin-dependent. It was originally identified in vascular endothelial cells, in which it generates NO in response to physiological stimuli such as the activation of membrane receptors.
The NO produced by the neuronal and endothelial constitutive isoforms (NOS-1 and NOS-3) is generally involved in intercellular signalling functions. For example, the endothelial cells which line the inner wall of the blood vessels induce the relaxation of the underlying smooth muscle cells via the production of NO. It thus contributes towards regulating the arterial pressure.
The NO produced in large amount by the inducible isoform NOS-2 is, inter alia, involved in pathological phenomena associated with acute and chronic inflammatory processes in a large variety of tissues and organs.
An excessive production of NO by induction of NOS-2 thus plays a part in degenerative pathologies of the nervous system such as, for example, multiple sclerosis, cerebral, focal or global ischemia, cerebral or spinal trauma, Parkinson""s disease, Huntington""s disease, Alzheimer""s disease, amiotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety and epilepsy. Similarly, aside from the central nervous system, the induction of NOS-2 is involved in numerous pathologies with inflammatory components, such as, for example, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma, irritable bowel syndrome, Crohn""s disease, peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barrxc3xa9 syndrome, glomerulonephritis, lupus erythematosus and psoriasis. NOS-2 has also been implicated in the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinoma or sarcoma, and in infections with Gram-positive or Gram-negative intracellular or extracellular bacteria.
In all the situations in which an overproduction of NO is deleterious, it thus appears to be desirable to reduce the production of NO by administering substances capable of inhibiting NOS-2. However, given the important physiological roles played by the constitutive isoform NOS-3, in particular in regulating arterial pressure, it is of fundamental importance that the inhibition of the isoform NOS-2 should have the least possible effect on the isoform NOS-3. The reason for this is that it is known that the administration of unselective inhibitors of the NOS isoforms leads to vasoconstriction and an increase in arterial pressure (Moncada, S., Palmer, R. M. J. and Higgs, E. A., Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication, Biochem. Pharmacol., 1989, 38: 1709-1715). These effects on the cardiovascular system are deleterious since they reduce the supply of nutrients to the tissues. Consequently, the present invention relates to compounds whose inhibitory activity with respect to NOS-2 is significantly higher than their inhibitory activity with respect to NOS-3.
Thiazoline-based NOS inhibitors are described in particular in patent applications WO 94/12165, WO 95/11231 and WO 96/14842.
The present invention relates to the use of 2-aminothiazoline derivatives of formula (I) in which: either R1 is a hydrogen atom or an alkyl radical and R2 is an alkyl, -alk-NH2, xe2x80x94CH2xe2x80x94R3, xe2x80x94CH2xe2x80x94Sxe2x80x94R4 or phenyl radical substituted with a nitro or xe2x80x94NHxe2x80x94C(xe2x95x90NH)CH3 radical,
or R1 is an alkyl radical and R2 is a hydrogen atom, R3 is a (3-6C) cycloalkyl, pyridyl, pyridyl N-oxide, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro or carboxyl radical,
R4 represents a pyridyl or pyridyl N-oxide radical, alk represents an alkylene radical for the preparation of medicinal products that are useful for preventing or treating diseases in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 or iNOS) is involved.
In the above definitions and in those which follow, the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or branched chain.
The compounds of formula (I) contain one or more asymmetric carbons and can thus be in racemic form or in the form of enantiomers and diastereoisomers; these also form part of the invention, along with mixtures thereof.
Moreover, the compounds of formula (I) can be in the tautomeric form (Ia): 
These tautomers also form part of the invention.
Among the compounds of formula (I) that are useful according to the invention, mention may be made of the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide
the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts thereof, and most particularly the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(5S)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
The compounds which are particularly preferred are the useful compounds of formula (I) according to the invention for which R1 is a hydrogen atom or an alkyl radical and R2 is an -alk-NH2 radical or a phenyl radical substituted with an xe2x80x94NHxe2x80x94C(xe2x95x90NH)CH3, xe2x80x94CH2xe2x80x94R3 or xe2x80x94CH2xe2x80x94Sxe2x80x94R4 radical and R3 is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or phenyl radical substituted with a nitro or carboxyl radical, R4 is a pyridyl radical.
In particular, when R2 is a xe2x80x94CH2xe2x80x94R3 or xe2x80x94CH2xe2x80x94Sxe2x80x94R4 chain, R3 is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position xe2x88x923 with a nitro or carboxyl radical and R4 is a 4-pyridyl radical.
Among the compounds which are useful according to the invention and particularly preferred, mention may be made of the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-imino-ethyl)amine
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof, as well as the pharmaceutically acceptable salts thereof, and in particular the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
The compounds of formula (I) for which R1 is methyl or hexyl and R2 is hydrogen or else R1 and R2 are methyl are known as chemical products (J. Org. Chem., 27, 1049 (1962); J. Org. Chem., 37, 4401 (1972); Beilstein Registry Numbers 6114855, 6114856, 6117694, 6117695).
Moreover, certain compounds of formula (I) are known as radioprotective agents. These are the racemic compounds for which
R1 is a methyl radical and R2 is a hydrogen atom (Chem. Abst., 1980, 92, 209060 and 209061),
R1 is hydrogen and R2 is methyl (Chem. Abst., 1997, 87, 193910),
R1 is hydrogen and R2 is ethyl (Khim. Geterotsikl. Soedin, 1987, 11, 1572),
R1 is hydrogen and R2 is n-propyl (Radiobiologiya, 1979, 19 (5), 671).
The other compounds of formula (I) are novel and, as such, they form part of the invention, as do the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof and the pharmaceutically acceptable salts thereof.
These are the compounds for which either R1 is a hydrogen atom or an alkyl radical and R2 is an alkyl, -alk-NH2, xe2x80x94CH2xe2x80x94R3 or xe2x80x94CH2xe2x80x94Sxe2x80x94R4 radical or a phenyl radical substituted with a nitro or xe2x80x94NHxe2x80x94C(xe2x95x90NH)CH3 radical,
or R1 is an alkyl radical and R2 is a hydrogen atom,
R3 is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro, hydroxyl or carboxyl radical,
R4 represents a pyridyl radical,
alk represents an alkylene radical,
the racemic mixtures, enantiomers and diastereoisomers thereof and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof,
with the exception of the compounds for which R1 is hexyl or methyl and R2 is hydrogen or else R1 and R2 are methyl, and the racemic mixtures of the compounds for which R1 is hydrogen and R2 is methyl, ethyl or n-propyl.
The compounds of formula (I) that are particularly preferred are those for which R1 is a hydrogen atom or an alkyl radical and R2 is an -alk-NH2 radical, a phenyl radical substituted with an xe2x80x94NHxe2x80x94C(xe2x95x90NH)CH3 radical, a radical xe2x80x94CH2xe2x80x94R3 for which R3 is a pyridyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl or phenyl radical or a phenyl radical substituted with a nitro or carboxyl radical, or a radical xe2x80x94CH2xe2x80x94Sxe2x80x94R4 for which R4 is a pyridyl radical, the racemic mixtures, enantiomers and diastereoisomers thereof and mixtures thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof.
In particular, R3 is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radical substituted in position xe2x88x923 with a nitro or carboxyl radical and R4 is a 4-pyridyl radical.
Among the novel compounds of formula (I) which may be mentioned are the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol -2-ylamine
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the racemic mixtures, enantiomers, diastereoisomers and tautomers thereof and the pharmaceutically acceptable salts thereof, and in particular the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-imino-ethyl)amine
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R))-5-methyl)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R,5R))-5-ethyl)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(xe2x88x92)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
the tautomers thereof and the pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutical compositions containing, as active principle, a derivative of formula (I) for which
either R1 is a hydrogen atom or an alkyl radical and R2 is an alkyl, -alk-NH2, xe2x80x94CH2xe2x80x94R3 or xe2x80x94CH2xe2x80x94Sxe2x80x94R4 radical or a phenyl radical substituted with a nitro or xe2x80x94NHxe2x80x94C(xe2x95x90NH)CH3 radical,
or R1 is an alkyl radical and R2 is a hydrogen atom,
R3 is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro, hydroxyl or carboxyl radical,
R4 represents a pyridyl radical and alk represents an alkylene radical,
as well as the racemic mixtures, enantiomers and diastereoisomers thereof and mixtures thereof, the tautomer thereof and the pharmaceutically acceptable salts thereof,
with the exception of the racemic compounds for which R1 is a methyl radical and R2 is a hydrogen atom or else R1 is hydrogen and R2 is methyl, ethyl or n-propyl.
The compounds of formula (I) can be prepared by cyclization of a derivative of formula: 
in which R1 and R2 have the same meanings as in formula (I).
This cyclization is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature of 100xc2x0 C. 6N hydrochloric acid is preferably used.
The derivatives of formula (II) can be obtained according to the following reaction schemes: Scheme 1 for the compounds for which R1 is hydrogen 
in these formulae R2 has the same meanings as in formula (I), Ra is a hydrogen atom or a protecting group for the amine function, such as those described by T. W. Greene, Protective groups in organic synthesis, J. Wiley-Interscience Publication (1991) and Rb is a (1-4C) alkyl or alkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl. The protecting group for the amine function is preferably an acetyl or tert-butoxycarbonyl radical.
Reaction a is generally carried out in the presence of a sodium (1-4C) alkoxide (preferably sodium ethoxide), in the corresponding alcohol, at a temperature of between 10xc2x0 C. and the boiling point of the reaction medium.
Reaction b is generally carried out in an inert solvent such as dimethylformamide in the presence of lithium iodide, at a temperature of between 100xc2x0 C. and the boiling point of the reaction medium, or in a (1-4C) aliphatic alcohol, in the presence of sodium hydroxide, at a temperature from 10xc2x0 C. to 30xc2x0 C., followed by neutralizing with 6N HCl then heating in a solvent such as dioxane at a temperature in the region of 100xc2x0 C.
Reaction bxe2x80x2 is preferably carried out using hydrochloric acid, at a temperature of 100xc2x0 C.
Reaction bxe2x80x3 for the derivatives for which Rb is an alkyl radical is generally carried out by the action of a (1-4C) aliphatic alcohol (preferably methanol or ethanol), in the presence of an inorganic acid such as sulfuric acid, at a temperature of between 50xc2x0 C. and the boiling point of the reaction medium. For the derivatives for which Rb is an isobutyloxycarbonyl radical, this reaction is generally carried out by the action of isobutyl chloroformate in the presence of a base such as triethylamine, in an inert solvent such as tetrahydrofuran, at a temperature of between xe2x88x9220xc2x0 C. and 0xc2x0 C.
The reduction reactions c, g and i are preferably carried out using a hydride such as sodium borohydride or lithium aluminum hydride, in a (1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of between 10xc2x0 C. and 30xc2x0 C., or alternatively using a borane derivative such as the BH3-THF complex, in a solvent such as tetrahydrofuran, at a temperature of between 0xc2x0 C. and 30xc2x0 C.
The deprotection reaction d for the compounds for which Ra is a protecting group for the amine function is carried out by any deprotection method known to those skilled in the art, and in particular those described by T. W. Greene, Protective groups in organic synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out using aqueous hydrochloric acid, at a temperature of 100xc2x0 C. When the protecting group is a tert-butoxycarbonyl radical, this reaction is carried out using hydrochloric acid in dioxane, at a temperature in the region of 20xc2x0 C.
Reactions e and h are carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as a (1-4C) aliphatic alcohol (preferably methanol or ethanol), optionally in the presence of a tertiary amine such as triethylamine, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Reaction f is carried out by the action of a (1-4C) aliphatic alcohol (preferably methanol or ethanol), in the presence of an inorganic acid such as hydrochloric acid, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium, or alternatively by the action of thionyl chloride, in a (1-4C) aliphatic alcohol (preferably methanol or ethanol), at a temperature of between 25xc2x0 C. and 30xc2x0 C. Scheme 2 for the compounds for which R1 is alkyl 
in these formulae R1 and R2 have the same meanings as in formula (I), Ra is a hydrogen atom or a protecting group for the amine function, such as those described by T. W. Greene, Protective groups in organic synthesis, J. Wiley-Interscience Publication (1991) and preferably an acetyl or tert-butoxycarbonyl radical, and Rb is an alkyl or alkoxycarbonyl radical, and preferably methyl, ethyl or isobutyloxycarbonyl.
Reaction a is preferably carried out in an inert solvent such as a chlorinated solvent (for example chloroform or dichloromethane), optionally in the presence of a base such as N-methylmorpholine or triethylamine, at a temperature of between xe2x88x9215xc2x0 C. and 30xc2x0 C.
Reaction b is carried out by the action of an alkylmagnesium halide such as an alkylmagnesium bromide, in an ether such as tetrahydrofuran or ethyl ether, at a temperature of between 0xc2x0 C. and 30xc2x0 C.
The reduction reaction c is preferably carried out using a hydride such as sodium borohydride or lithium aluminum hydride, in a (1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of between 10xc2x0 C. and 30xc2x0 C., or using a borane derivative such as the BH3-THF complex, in a solvent such as tetrahydrofuran, at a temperature of between 0xc2x0 C. and 30xc2x0 C.
The deprotection reaction d is carried out by any method known to those skilled in the art for deprotecting an amine function, and in particular those described by T. W. Greene, Protective groups in organic synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out using aqueous hydrochloric acid, at a temperature of 100xc2x0 C. When the protecting group is a tert-butoxycarbonyl radical, this reaction is carried out using hydrochloric acid in dioxane, at a temperature in the region of 20xc2x0 C.
Reaction e is carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as a (1-4C) aliphatic alcohol (preferably methanol or ethanol), in the presence of a tertiary amine such as triethylamine, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
The compounds of formula (I) for which R2 is a phenyl radical substituted with an xe2x80x94NHxe2x80x94C(xe2x95x90NH)CH3 radical can also be prepared from the corresponding amine derivatives which are themselves obtained by reducing the nitro derivatives of formula (I) according to the following scheme: 
The reduction reaction a is carried out by any reduction method known to those skilled in the art for proceeding from a nitro to an amino without affecting the rest of the molecule. The process is preferably performed using zinc, in acetic acid, at a, temperature in the region of 20xc2x0 C.
Reaction b is carried out by reaction of benzyl ethanimidothioate hydrochloride, in an inert solvent such as a (1-4C) aliphatic alcohol and preferably methanol or ethanol, at a temperature of between 0xc2x0 C. and 45xc2x0 C.
The intermediates of formula (III) are novel and form part of the invention.
The compounds of formula (I) for which R2 is a radical xe2x80x94CH2xe2x80x94R3 in which R3 is a 1-imidazolyl or 1-(1,2,4-triazolyl) radical may also be prepared by the action of imidazolyl or of 1,2,4-triazole on a derivative of formula: 
in which R1 has the same meanings as in formula (I), X is a halogen atom, and in particular an iodine atom, or a tosyl radical, Ra and Rb are hydrogen atoms or protecting groups for the amine function such as those described by T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butoxycarbonyl, optionally followed by a deprotection.
This reaction is generally carried out in the presence of a base such as an alkali metal hydride, preferably sodium hydride, in a solvent such as dimethyl sulfoxide, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
The deprotection reaction for the compounds for which Ra or Rb is a protecting group for the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out using aqueous hydrochloric acid, at a temperature of 100xc2x0 C. When the protecting group is a tert-butoxycarbonyl radical, this reaction is carried out using hydrochloric acid in dioxane, at a temperature in the region of 20xc2x0 C.
The compounds of formula (IV) may themselves be obtained according to the following reaction scheme: 
In these formulae, R1 has the same meaning as in formula (I), Ts is a tosylate radical, Ra and Rb are a hydrogen atom or a protecting group for the amine function such as those described by T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butoxycarbonyl.
Reaction a is generally carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as an aliphatic alcohol (1-4C) (preferably methanol or ethanol), optionally in the presence of a tertiary amine such as triethylamine, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Cyclization reaction b is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature in the region of 100xc2x0 C. 6N hydrochloric acid is preferably used.
When Ra or Rb is a tert-butoxycarbonyl group, reactions c and g are carried out by any protection method known to those skilled in the art and in particular those described by T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). This reaction is preferably carried out using di-tert-butyl dicarbonate, in the presence of a base such as triethylamine and optionally in the presence of 4-(dimethylamino)pyridine, in a solvent such as dichloromethane and at a temperature in the region of 20xc2x0 C., or alternatively in the presence of a base such as potassium carbonate, in a solvent such as water and at a temperature in the region of 20xc2x0 C.
Reaction d is generally carried out by the action of p-toluenesulfonyl chloride, in the presence of a tertiary amine such as triethylamine, in an inert solvent such as dichloromethane, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Reaction e is generally carried out by the action of sodium iodide, in an inert solvent such as acetone, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Reaction f is generally carried out by the action of an allyl halide, for example allyl chloride, in an aliphatic alcohol (1-4C), preferably ethanol, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Reaction h is generally carried out by the action of iodine, in the presence of base such as sodium bicarbonate, in a solvent such as dichloromethane, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
The compounds of formula (I) for which R2 is a radical xe2x80x94CH2xe2x80x94Sxe2x80x94R4 may be prepared by the action of a corresponding compound of formula (IVa) or (IVb) with a derivative of formula HS-R4 in which R4 has the same meaning as in formula (I) and Ra and Rb are hydrogen atoms or protecting groups for the amine function such as those described by T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butoxycarbonyl, optionally followed by a deprotection of the amine function.
This reaction is generally carried out in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile or dimethylformamide (preferably acetonitrile), at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
The deprotection reaction for the compounds for which Ra or Rb is a protecting group for the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out using aqueous hydrochloric acid, at a temperature of 100xc2x0 C. When the protecting group is a tert-butoxycarbonyl radical, this reaction is carried out using hydrochloric acid in dioxane, at a temperature in the region of 20xc2x0 C. The compounds of formula (I) are isolated and may be purified by the usual known methods, for example by crystallization, chromatography or extraction.
The enantiomers of the compounds of formula (I) can be obtained by resolving the racemic mixtures, for example by chromatography on a chiral column according to Pirckle W. H. et al., Asymmetric Synthesis, Vol. 1, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers can be prepared according to the known conventional methods (crystallization or chromatography or from chiral precursors).
The compounds of formula (I) can optionally be converted into addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention.
Examples of pharmaceutically acceptable salts which may be mentioned are the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylenebis-xcex2-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate.
The compounds of formula (I) are inhibitors of inducible NO-synthase or type-2 NO-synthase (NOS-2) and are thus useful for preventing and treating disorders associated with excessive NO production, such as multiple sclerosis, cerebral, focal or global ischemia, cerebral or spinal trauma, Parkinson""s disease, Huntington""s disease, Alzheimer""s disease, amiotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety and epilepsy, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma, irritable bowel syndrome, Crohn""s disease, peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barrxc3xa9 syndrome, glomerulonephritis, lupus erythematosus, psoriasis, the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinomas or sarcomas, and infections with Gram-positive or Gram-negative intracellular or extracellular bacteria.
Their activities as NOS-2 and NOS-3 inhibitors were determined by measuring the conversion of [3H]-L-arginine into [3H]-L-citrulline with, respectively, an NOS-2 enzymatic fraction extracted from the lungs of rats or mice pretreated with lipopolysaccharides (10 mg/kg i.p. 6 hours before collecting the tissue) and with a commercial preparation of recombinant bovine NOS-3. The compounds were incubated for 20 to 30 minutes at 37xc2x0 C. in the presence of 5 xcexcM (for NOS-2 activity) or 10 xcexcM (for NOS-3 activity) of [3H]-L-arginine, 1 mM of NADPH, 15 xcexcM of tetrabiopterine, 1 xcexcM of FAD, 0.1 mM of DTT in a HEPES buffer (50 mM, pH 6.7) containing 10 xcexcg/ml of calmodulin and 1.25 mM of CaCl2 when the NOS-3 activity was measured. The incubation was stopped by adding cold HEPES buffer (100 mM, pH 5.5) containing 10 mM of EGTA and 500 mg of a cationic ion-exchange resin (AG50W-X8, counterion: Na+) to separate the [3H]-L-arginine from the [3H]-L-citrulline. After separation of the phases by settling for 5 min, the radioactivity remaining in the liquid phase was measured in a scintillation counter in the presence of a suitable scintillation liquid. The yield for the recovery of the [3H]-L-citrulline formed was able to be estimated using [14C-ureido]-L-citrulline as external standard. The NOS-2 or NOS-3 activity was expressed in picomole(s) of [3H]-L-citrulline formed per minute and per milligram of protein contained in the reaction medium.
In this test on the enzyme NOS-2, the IC50 value for the compounds of formula (I) is less than or equal to 10 xcexcM.
The selectivity is measured by the NOS-3 IC50/NOS-2 IC50 ratio. This selectivity is greater than 20.
The compounds of formula (I) are of low toxicity. Their LD50 value is greater than 40 mg/kg via the cutaneous route in mice.
The examples which follow illustrate the invention.